a-synuclein (aSyn) is an intrinsically disordered protein that appears in aggregated form in the brains of patients with Parkinson's disease. The conversion of monomer to aggregate is complex. Aggregation rates of aSyn are very sensitive to changes in amino acid sequence and environmental conditions. Understanding aSyn aggregation requires characterizing the ensemble of conformations adopted by the monomer and correlating them to aggregation behavior. Though many hypotheses have been proposed to relate aSyn's aggregation behavior to its interconverting conformational ensembles, a consistent molecular description of the aSyn conformational ensembles and their relationship to aggregation remains elusive. This proposal integrates NMR and computational approaches to characterize and explicitly visualize the intrinsically disordered conformational ensembles of aSyn and the early stages of aggregation under different sequence and environmental conditions. The goal is to identify the elements of transient 2o and/or 3o structure that are key for initiation of aggregation and determine their stabilizing driving forces. Identifying the structural basis of aSyn monomer aggregation propensity may be critical for developing inhibitors for the aggregation steps that precede the toxic aggregation cascade. Once developed, this integrated approach can be applied to other important biological functions or diseases involving intrinsically disordered proteins. PUBLIC HEALTH RELEVANCE: Parkinson's disease is the second most prevalent of the late onset neurodegenerative diseases. a-synuclein, an extremely important protein involved in the etiology of Parkinson's disease will be modeled at the molecular level by integrating NMR and computational approaches. Understanding the role of the monomeric conformational ensembles of a-synuclein may be critical for developing inhibition strategies against amyloid formation.